Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor

ABSTRACT

The present invention relates to processes for preparing pyrazole derivatives of Formula (I) and salts and pharmaceutical compositions of the salts thereof, useful as modulators of 5-HT 2A  serotonin receptor activity. 
     
       
         
         
             
             
         
       
     
     The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to salts of compounds of Formula (I) and pharmaceutical compositions thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/523,224 filed Oct. 24, 2014, which is a continuation of U.S. NationalPhase Application 12/936,038, filed Oct. 1, 2010, which is a § 371National Stage Application of International Application PCT/US09/02019,filed Apr. 1, 2009, which claims the benefit of priority of U.S.Provisional Application No. 61/072,697, filed Apr. 2, 2008, each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes for preparing pyrazolederivatives of Formula (I) and salts and pharmaceutical compositions ofthe salts thereof, useful as modulators of 5-HT_(2A) serotonin receptoractivity. The present invention also relates to intermediates used inthe processes, and their preparation. The present invention also relatesto salts of compounds of Formula (I) and pharmaceutical compositionsthereof.

BACKGROUND OF THE INVENTION

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein coupled receptors. Serotonin receptors are dividedinto seven subfamilies, referred to as 5-HT₁ through 5-HT₇, inclusive.These subfamilies are further divided into subtypes. For example, the5-HT₂ subfamily is divided into three receptor subtypes: 5-HT_(2A),5-HT_(2B), and 5-HT_(2C). Certain pyrazole derivatives are modulators of5-HT_(2A) serotonin receptor activity useful in the treatment ofinsomnia and related sleep disorders, platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, atrial fibrillation, reducing the risk of blood clotformation, asthma or symptoms thereof, agitation or symptoms thereof,behavioral disorders, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorders, psychosis, acute schizophrenia, chronicschizophrenia, NOS schizophrenia and related disorders, diabetic-relateddisorders, progressive multifocal leukoencephalopathy and the like.

SUMMARY OF THE INVENTION

One aspect of the present invention pertains to processes for preparingcompounds of Formula (I):

or a salt thereof, wherein:

R¹ is halogen;

comprising reacting a compound of Formula (II):

or a salt thereof, with a compound of Formula (III):

or a salt thereof, wherein:

R² is a leaving group;

to form a compound of Formula (I) or a salt thereof.

One aspect of the present invention pertains to processes for preparingcompounds of Formula (II) or a salt thereof, comprising reacting acompound of Formula (IV):

wherein:

R³ is halogen, C₁-C₆ alkylsulfonyloxy or arylsulfonyloxy; wherein saidarylsulfonyloxy may be further substituted with C₁-C₆ alkyl;

with a compound of Formula (V):

or a salt thereof, to form a compound of Formula (II) or a salt thereof.

One aspect of the present invention pertains to processes for preparingcompounds of Formula (III) or a salt thereof, comprising reacting acompound of Formula (VI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to form a compound of Formula (III) or a saltthereof.

The present invention further provides processes for preparing compoundsof Formula (I) or a salt thereof, comprising the steps:

(a) reacting a compound of Formula (VI) or a salt thereof, with acompound of Formula (VII) or a salt thereof, wherein to form a compoundof Formula (III) or a salt thereof; and

(b) further reacting the compound of Formula (III) or a salt thereof insitu with a compound of Formula (III) or a salt thereof, to form acompound of Formula (I) or a salt thereof.

One aspect of the present invention pertains to processes for preparingsalts of compounds of Formula (I):

comprising reacting a compound of Formula (I) with a salt-forming acidto form a salt of a compound of Formula (I).

One aspect of the present invention pertains to hydrochloride salts ofcompounds of Formula (I) prepared by the processes described herein.

In some embodiments the present invention provides(S)-2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanonehydrochloride, represented by the following structure:

In some embodiments the present invention provides(R)-2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanonehydrochloride, represented by the following structure:

In some embodiments the present invention provides(S)-2-(4-(4-bromo-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanonehydrochloride, represented by the following structure:

In some embodiments the present invention provides(R)-2-(4-(4-bromo-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanonehydrochloride, represented by the following structure:

One aspect of the present invention pertains to pharmaceuticalcompositions comprising compounds of Formula (I) prepared by theprocesses described herein.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a hydrochloride salt of a compound of Formula(I) and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) mediated disorder in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of ahydrochloride salt as described herein.

One aspect of the present invention pertains to methods for treatingcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a hydrochloride salt as describedherein.

One aspect of the present invention pertains to methods for treating asleep disorder in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of ahydrochloride salt as described herein.

One aspect of the present invention pertains to methods for treating adyssomnia in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a hydrochloride saltas described herein.

One aspect of the present invention pertains to methods for treatinginsomnia in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a hydrochloride saltas described herein.

One aspect of the present invention pertains to methods for treating aparasomnia in an individual comprising administering to the individualin need thereof a therapeutically effective amount of a hydrochloridesalt as described herein.

One aspect of the present invention pertains to methods for increasingslow wave sleep in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of ahydrochloride salt as described herein.

One aspect of the present invention pertains to methods for improvingsleep consolidation in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of ahydrochloride salt as described herein.

One aspect of the present invention pertains to methods for improvingsleep maintenance in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of ahydrochloride salt as described herein.

One aspect of the present invention pertains to methods for treating asleep disorder selected from: a dyssomnia, insomnia or a parasomnia; orfor increasing slow wave sleep, improving sleep consolidation orimproving sleep maintenance in an individual comprising administering tosaid individual in need thereof a therapeutically effective amount ofthe hydrochloride salt as described herein.

One aspect of the present invention pertains to methods for treating acondition associated with platelet aggregation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a hydrochloride salt as describedherein.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa hydrochloride salt as described herein.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to the individual in needthereof a therapeutically effective amount of a hydrochloride salt asdescribed herein.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation, comprising administering to the individual in need thereofa therapeutically effective amount of a hydrochloride salt as describedherein.

One aspect of the present invention pertains to methods for treating adiabetic-related disorder in an individual suffering from atrialfibrillation, comprising administering to the individual in need thereofa therapeutically effective amount of a hydrochloride salt as describedherein.

One aspect of the present invention pertains to methods for treatingprogressive multifocal leukoencephalopathy in an individual sufferingfrom atrial fibrillation, comprising administering to the individual inneed thereof a therapeutically effective amount of a hydrochloride saltas described herein.

One aspect of the present invention pertains to methods for treatinghypertension in an individual suffering from atrial fibrillation,comprising administering to the individual in need thereof atherapeutically effective amount of a hydrochloride salt as describedherein.

One aspect of the present invention pertains to methods for treatingpain in an individual suffering from atrial fibrillation, comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a hydrochloride salt as described herein.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a sleep disorder.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a dyssomnia.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of insomnia.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a parasomnia.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament forincreasing slow wave sleep.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament forimproving sleep consolidation.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament forimproving sleep maintenance.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a sleep disorder selected from: a dyssomnia, insomnia or aparasomnia; or for the manufacture of a medicament for increasing slowwave sleep, improving sleep consolidation or improving sleepmaintenance.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a 5-HT_(2A) mediated disorder.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a 5-HT_(2A) mediated disorder selected from the groupconsisting of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, and atrial fibrillation.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a condition associated with platelet aggregation.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thereduction of the risk of blood clot formation.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thereduction of the risk of blood clot formation in an angioplasty orcoronary bypass surgery individual.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thereduction of the risk of blood clot formation in an individual sufferingfrom atrial fibrillation.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of a diabetic-related disorder.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of progressive multifocal leukoencephalopathy.

One aspect of the present invention pertains to use of hydrochloridesalts as described herein for the manufacture of a medicament for thetreatment of hypertension.

One aspect of the present invention pertains to use of a hydrochloridesalt as described herein for the manufacture of a medicament for thetreatment of pain.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of the human or animalbody by therapy.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a 5-HT_(2A)mediated disorder.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a 5-HT_(2A)mediated disorder selected from the group consisting of coronary arterydisease, myocardial infarction, transient ischemic attack, angina,stroke, and atrial fibrillation.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a sleep disorder.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a dyssomnia.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of insomnia.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a parasomnia.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method for increasing slow wave sleep.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method for improving sleep consolidation.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method for improving sleep maintenance.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a sleep disorderselected from: a dyssomnia, insomnia or a parasomnia; or for use in amethod for increasing slow wave sleep, improving sleep consolidation orimproving sleep maintenance.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a conditionassociated with platelet aggregation.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of reducing the risk of blood clotformation.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of reducing the risk of blood clotformation in an angioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of reducing the risk of blood clotformation in an individual suffering from atrial fibrillation.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of a diabetic-relateddisorder.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of progressivemultifocal leukoencephalopathy.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of hypertension.

One aspect of the present invention pertains to hydrochloride salts asdescribed herein for use in a method of treatment of pain.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a hydrochloride salt as describedherein and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to hydrobromide salts of acompound of Formula (II) prepared by the processes described herein.

One aspect of the present invention pertains to compounds of Formula(III):

and salts thereof, wherein:

R¹ is halogen; and

R² is 1H-imidazolyl;

prepared by the processes described herein.

DETAILED DESCRIPTION

Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonists” is intended to mean moieties that interact andactivate the receptor, such as the 5-HT_(2A) serotonin receptor, andinitiate a physiological or pharmacological response characteristic ofthat receptor. For example, when moieties activate the intracellularresponse upon binding to the receptor, or enhance GTP binding tomembranes.

The term “antagonists” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

The term “hydrate” as used herein means a salt of the invention thatfurther includes a stoichiometric or non-stoichiometric amount of waterbound by non-covalent intermolecular forces.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the salts ofthe invention. Accordingly, the salts of the invention can be used in aprotective or preventive manner; or salts of the invention can be usedto alleviate, inhibit or ameliorate the disease, condition or disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

The term “inverse agonists” is intended to mean moieties that bind tothe endogenous form of the receptor or to the constitutively activatedform of the receptor, and which inhibit the baseline intracellularresponse initiated by the active form of the receptor below the normalbase level of activity which is observed in the absence of agonists orpartial agonists, or decrease GTP binding to membranes. Preferably, thebaseline intracellular response is inhibited in the presence of theinverse agonist by at least 30%, more preferably by at least 50%, andmost preferably by at least 75%, as compared with the baseline responsein the absence of the inverse agonist.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited tosalts of the present invention and solvates and hydrates thereof;whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “solvate” as used herein means a salt of the invention thatfurther includes a stoichiometric or non-stoichiometric amount of asolvent bound by non-covalent intermolecular forces. Preferred solventsare volatile, non-toxic, and/or acceptable for administration to humansin trace amounts.

The term “substituted” as used herein indicates that at least onehydrogen atom of the chemical group is replaced by a non-hydrogensubstituent or group, the non-hydrogen substituent or group can bemonovalent or divalent. When the substituent or group is divalent, thenit is understood that this group is further substituted with anothersubstituent or group.

When a chemical group herein is “substituted” it may have up to the fullvalance of substitution; for example, a methyl group can be substitutedby 1, 2, or 3 substituents, a methylene group can be substituted by 1 or2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6,or 7 substituents and the like.

The term “therapeutically effective amount” is intended to mean theamount of active salt or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician or caregiver; or by an individual, whichincludes one or more of the following:

(1) Preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical

The term “C₁-C₆ acyl” refers to a C₁₋₆ alkyl radical attached directlyto the carbon of a carbonyl group wherein the definition for alkyl is asdescribed herein; some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, isobutanoyl, pivaloyl, pentanoyl and the like.

The term “C₁-C₆ acyloxy” refers to an acyl radical attached directly toan oxygen atom [—OC(═O)—C₁-C₆ alkyl] wherein acyl has the samedefinition has described herein; some examples include but are notlimited to acetyloxy [—OC(═O)CH₃], propionyloxy, butanoyloxy,isobutanoyloxy, pivaloyloxy and the like.

The term “C₁-C₆ alkoxy” is intended to mean a C₁-C₆ alkyl radical, asdefined herein, attached directly to an oxygen atom. Some embodimentsare 1 to 5 carbons; some embodiments are 1 to 4 carbons; someembodiments are 1 to 3 carbons; and some embodiments are 1 or 2 carbons.Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,t-butoxy, isobutoxy, sec-butoxy and the like.

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons.Some embodiments are 1 to 4 carbons. Some embodiments are 1 to 3carbons. Some embodiments are 1 or 2 carbons. Some embodiments are 1carbon. Examples of an alkyl include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,pentyl, isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁-C₆ alkylsulfonyloxy” is intended to mean the group shownbelow wherein C₁-C₆ alkyl has the same definition as used herein:

Examples of C₁-C₆ alkylsulfonyloxy include, but are not limited to,methylsulfonyloxy, ethylsulfonyloxy and the like.

The term “C₁-C₆ arylsulfonyloxy” is intended to mean the group shownbelow wherein C₁-C₆ alkyl has the same definition as used herein:

Examples of arylsulfonyloxy include but are not limited tophenylsulfonyloxy naphthylsulfonyloxy and the like.

The term “halogen” or “halo” is intended to mean to a fluoro, chloro,bromo or iodo group.

The term “heteroaryl” is intended to mean an aromatic ring system thatmay be a single ring, two fused rings or three fused rings wherein atleast one ring atom is a heteroatom selected from, but not limited to,the group consisting of O, S and N. Examples of heteroaryl groupsinclude, but are not limited to, pyridyl, benzofuranyl, pyrazinyl,pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl,benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl, quinazolinyl,quinoxalinyl, and the like. In some embodiments, the heteroaryl groupcontains a heteroatom selected from, for example, the group consistingof O, S and N, wherein N is substituted with H (i.e., NH). Examplesinclude, but are not limited to, pyrrolyl, indolyl,1H-benzoimidazol-2-yl, 1H-benzo[d][1,2,3]triazol-1-yl and the like.

The term “heterocyclyl” or “heterocyclic” is intended to mean a ringsystem containing 3 to 15 ring atoms that may be a single ring, twofused rings or three fused rings, wherein at least one ring atom is aheteroatom or substituted heteroatom selected from, but not limited to,the group consisting of O, S, S(═O), S(═O)₂ and NH. In some embodiments,the ring carbon atoms are optionally substituted with oxo thus forming acarbonyl group. In some embodiments the heterocyclic group is a 3-, 4-,5-, 6- or 7-membered ring. In some embodiments the heterocyclic group isa bicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. In some embodiments the heterocyclic group is atricyclic group in which any of the above-defined heterocyclic rings isfused to two benzene rings. Examples of a heterocyclic group include,but are not limited to: [1,4]-oxazepanyl,10,11-dihydro-5H-dibenzo[b,f]azepinyl, azepanyl, azetidinyl, aziridinyl,imidazolidinyl, imidazolinyl, indolinyl, morpholinyl, piperidinyl,piperazinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,succinimidyl, thiomorpholinyl, and the like. In some embodiments aheterocyclic group can be bonded only at a ring carbon or ring nitrogenas allowed by the respective formulae unless otherwise specified. Insome embodiments a heterocyclic group can be bonded only at a ringnitrogen as allowed by the respective formulae unless otherwisespecified.

The term “heteroaryloxy” is intended to mean an oxygen radical furthersubstituted with a heteroaryl group as defined herein.

The term “heterocyclyloxy” is intended to mean an oxygen radical furthersubstituted with a heterocyclic group as defined herein.

The term “leaving group” is a term well known to the skilled chemist,examples being halogens such as chloro, bromo and iodo; C₁-C₆ acyloxygroups such as acetyloxy, pivaloyloxy and the like; C₁-C₆ alkoxy groupssuch as methoxy, ethoxy, isopropoxy and the like; N-linked heteroarylgroups such as 1H-imidazol-1-yl and the like; heteroaryloxy groups suchas 1H-benzo[d][1,2,3]triazol-1-yloxy and the like; and heterocyclyloxygroups such as 2,5-dioxopyrrolidin-1-yloxy and the like. In someembodiments, the term leaving group is intended to mean a leaving groupother than chloro. In some embodiments, the term leaving group isintended to mean a leaving group other than3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy. In some embodiments, the termleaving group is intended to mean a leaving group other than the leavinggroup formed upon activation of a carboxylic acid with1-propylphosphonic anhydride.

The term “N-linked heteroaryl” is intended to mean monocyclic andpolycyclic aromatic ring radicals having at least one nitrogen ring atomthrough which the ring radical is bonded. Examples of N-linkedheteroaryl groups include but are not limited to 1H-imidazol-1-yl andthe like.

Processes of the Invention

The present invention is directed inter alia to processes andintermediates for the preparation of pyrazole derivatives that areuseful as modulators of 5-HT_(2A) serotonin receptor activity for thetreatment of disorders associated with 5-HT_(2A) serotonin receptorexpression and/or activity such as, for example, insomnia and relatedsleep disorders, platelet aggregation, coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, reducing the risk of blood clot formation, asthma orsymptoms thereof, agitation or symptoms thereof, behavioral disorders,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorder, organic or NOS psychosis, psychotic disorders,psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophreniaand related disorders, diabetic-related disorders, progressivemultifocal leukoencephalopathy and the like. The present inventionfurther provides processes for preparing pyrazole derivatives of Formula(I) and salts and pharmaceutical compositions thereof, and intermediatesused in the processes and their preparation.

Example processes and intermediates of the present invention areprovided below in Scheme I, wherein each constituent member of thecompounds depicted are defined herein.

One aspect of the present invention pertains to processes, such as thoseexemplified by Scheme I (supra), that involve compounds of Formulae (I),(II), (III), (IV), (V), (VI) and (VII) or salts thereof, wherein:

R¹ is halogen;

R² is a leaving group; and

R³ is halogen, C₁-C₆ alkylsulfonyloxy or arylsulfonyloxy; wherein saidarylsulfonyloxy may be further substituted with C₁-C₆ alkyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (R¹, R²and R³) contained within the generic chemical formulae described herein[(I), (II), (III), (IV), (V), (VI) and (VII)] are specifically embracedby the present invention just as if they were explicitly disclosed, tothe extent that such combinations embrace compounds that result instable compounds (i.e., compounds that can be isolated, characterizedand tested for biological activity).

One aspect of the present invention pertains to a process for preparinga compound of Formula (I):

or a salt thereof, comprising:

-   -   (a) reacting a compound of Formula (VI):

-   -   -   or a salt thereof, with a compound of Formula (VII):

-   -   -   or a salt thereof, to form a compound of Formula (III):

-   -   -   or a salt thereof;

    -   (b) reacting a compound of Formula (IV):

-   -   -   with a compound of Formula (V):

-   -   -   or a salt thereof, to form a compound of Formula (II):

-   -   -   or a salt thereof; and

    -   (c) reacting the compound of Formula (II) or a salt thereof,        with the compound of Formula (III) or a salt thereof, to form        the compound of Formula (I) or a salt thereof;        wherein:

R¹ is a halogen

R² is a leaving group; and

R³ is a halogen.

The Group R¹:

In some embodiments, R¹ is halogen.

In some embodiments, R¹ is fluoro.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, R¹ is iodo.

The Group R²:

In some embodiments, R² is a leaving group.

In some embodiments, R² is an N-linked heteroaryl.

In some embodiments, R² is 1H-imidazol-1-yl.

In some embodiments, R² is a leaving group other than chloro.

In some embodiments, R² is a leaving group other than3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy. It is understood that theleaving group 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy is the leavinggroup formed upon activation of a carboxylic acid withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU).

In some embodiments, R² is a leaving group other than the leaving groupformed upon activation of a carboxylic acid with 1-propylphosphonicanhydride.

The Group R³:

In some embodiments, R³ is halogen.

In some embodiments, R³ is fluoro.

In some embodiments, R³ is chloro.

In some embodiments, R³ is bromo.

In some embodiments, R³ is iodo.

In some embodiments, R³ is C₁-C₆ alkylsulfonyloxy.

In some embodiments, R³ is methylsulfonyloxy.

In some embodiments, R³ is arylsulfonyloxy.

In some embodiments, R³ is phenylsulfonyloxy.

In some embodiments, R³ is arylsulfonyloxy further substituted withC₁-C₆ alkyl.

In some embodiments, R³ is tosyloxy.

Certain Combinations of the Present Invention:

-   -   In some embodiments:        -   R¹ is chloro;        -   R² is 1H-imidazol-1-yl; and        -   R³ is bromo.    -   In some embodiments:        -   R¹ is bromo;        -   R² is 1H-imidazol-1-yl; and        -   R³ is bromo.            Amide-Forming Step

One aspect of the present invention pertains to processes for preparingcompounds of Formula (I):

or a salt thereof, comprising reacting a compound of Formula (II):

or a salt thereof, with a compound of Formula (III):

or a salt thereof, to form a compound of Formula (I) or a salt thereof.

In some embodiments, the compound of Formula (I) is the R enantiomer.

In some embodiments, the compound of Formula (I) is the S enantiomer.

In some embodiments, the compound of Formula (I) is selected from: the Renantiomer, the S enantiomer or a mixture thereof.

In some embodiments, the process comprises reacting a hydrobromide saltof a compound of Formula (II) with a compound of Formula (III) or a saltthereof to form a compound of Formula (I) or a salt thereof.

In some embodiments, the process comprises reacting a hydrochloride saltof a compound of Formula (II) with a compound of Formula (III) or a saltthereof to form a compound of Formula (I) or a salt thereof.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, R² is an N-linked heteroaryl.

In some embodiments, R² is 1H-imidazol-1-yl.

In some embodiments, R¹ is chloro and R² is 1H-imidazol-1-yl.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in the presence of a base.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (II) or a salt thereof is carriedout in the presence of a tertiary amine.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in the presence of triethylamine.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in the presence of a catalyst.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in the presence of 2-hydroxypyridine.

In some embodiments, the reacting a compound of Formula (I) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in the presence of N,N-dimethylaminopyridine.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout at a temperature of about 20° C. to about reflux temperature.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout at a temperature of about 40° C. to about reflux temperature.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout at a temperature of about 60° C. to about 80° C.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (II) or a salt thereof is carriedout in an amide-forming solvent.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in an aprotic solvent.

In some embodiments, the reacting a compound of Formula (II) or a saltthereof, with a compound of Formula (III) or a salt thereof is carriedout in acetonitrile.

In some embodiments, the molar ratio of the compound of Formula (II) tothe compound of Formula (III) is about 2:1 to about 0.5:1.

In some embodiments, the molar ratio of the compound of Formula (II) tothe compound of Formula (IL) is about 1:1.

Alkylation Step

One aspect of the present invention pertains to processes for preparingcompounds of Formula (II) comprising reacting a compound of Formula(IV):

with a compound of Formula (V):

or a salt thereof, to form a compound of Formula (II) or a salt thereof.

In some embodiments, the process forms a hydrobromide salt of a compoundof Formula (II).

In some embodiments, R³ is bromo.

In some embodiments, the process forms a hydrochloride salt of acompound of Formula (II).

In some embodiments, R³ is chloro.

In some embodiments, the compound of Formula (V) is the R enantiomer.

In some embodiments, the compound of Formula (V) is the S enantiomer.

In some embodiments, the compound of Formula (V) is selected from: the Renantiomer, the S enantiomer or a mixture thereof.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out in analkylating solvent.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out in a C₁-C₃alcohol.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out in ethanol.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out in isopropanol.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out at atemperature of about −20° C. to about 80° C.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out at atemperature of about 0° C. to about 60° C.

In some embodiments, the reacting a compound of Formula (IV) with acompound of Formula (V) or a salt thereof is carried out at atemperature of about 20° C. to about 50° C.

In some embodiments, the molar ratio of the compound of Formula (IV) tothe compound of Formula (V) is about 2:1 to about 1:2.

In some embodiments, the molar ratio of the compound of Formula (IV) tothe compound of Formula (V) is about 1:1 to about 1:1.2.

Carboxylic Acid Activation Step

One aspect of the present invention pertains to processes for preparingcompounds of Formula (III) or a salt thereof, comprising reacting acompound of Formula (VI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to form a compound of Formula (III) or a saltthereof.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, R² is an N-linked heteroaryl.

In some embodiments, R² is 1H-imidazol-1-yl.

In some embodiments, R¹ is chloro and R² is 1H-imidazol-1-yl.

In some embodiments, the reacting a compound of Formula (VI) or a saltthereof with a compound of Formula (VII) or a salt thereof is carriedout in a carboxylic acid activating solvent.

In some embodiments, the reacting a compound of Formula (VI) or a saltthereof with a compound of Formula (VII) or a salt thereof is carriedout in an aprotic solvent.

In some embodiments, the reacting a compound of Formula (VI) or a saltthereof with a compound of Formula (VII) or a salt thereof is carriedout in acetonitrile.

In some embodiments, the said reacting a compound of Formula (VI) or asalt thereof with a compound of Formula (VII) or a salt thereof iscarried out at a temperature of about 20° C. to about refluxtemperature.

In some embodiments, the reacting a compound of Formula (VI) or a saltthereof with a compound of Formula (VII) or a salt thereof is carriedout at a temperature of about 40° C. to about 70° C.

In some embodiments, the reacting a compound of Formula (VI) or a saltthereof with a compound of Formula (VII) or a salt thereof is carriedout at a temperature of about 50° C. to about 60° C.

In some embodiments, the molar ratio of the compound of Formula (VI) tothe compound of Formula (VII) is about 2:1 to about 1:2.

In some embodiments, the molar ratio of the compound of Formula (VI) tothe compound of Formula (VII) is about 1:1.

In Situ Carboxylic Acid Activation/Amide-Forming Step

One aspect of the present invention pertains to processes for preparingcompounds of Formula (I) or a salt thereof, comprising the steps:

(a) reacting a compound of Formula (VI) or a salt thereof, with acompound of Formula (VII) or a salt thereof, wherein to form a compoundof Formula (III) or a salt thereof; and

(b) further reacting the compound of Formula (I) or a salt thereof insitu with a compound of Formula (II) or a salt thereof, to form acompound of Formula (I) or a salt thereof.

In some embodiments, the compound of Formula (I) is the R enantiomer.

In some embodiments, the compound of Formula (I) is the S enantiomer.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, R² is an N-linked heteroaryl.

In some embodiments, R² is 1H-imidazol-1-yl.

In some embodiments, step (a) is carried out in a carboxylic acidactivating solvent.

In some embodiments, step (a) is carried out in an aprotic solvent.

In some embodiments, step (a) is carried out in acetonitrile.

In some embodiments, step (a) is carried out at a temperature of about20° C. to about reflux temperature.

In some embodiments, step (a) is carried out at a temperature of about40° C. to about 70° C.

In some embodiments, step (a) is carried out at a temperature of about50° C. to about 60° C.

In some embodiments, the molar ratio of the compound of Formula (VI) tothe compound of Formula (VII) is about 2:1 to about 1:2.

In some embodiments, the molar ratio of the compound of Formula (VI) tothe compound of Formula (VII) is about 1:1.

In some embodiments, the process comprises reacting the compound ofFormula (III) or a salt thereof in situ with a hydrobromide salt of acompound of Formula (III) to form a compound of Formula (I) or a saltthereof.

In some embodiments, the process comprises reacting said compound ofFormula (III) or a salt thereof in situ with a hydrochloride salt of acompound of Formula (II) to form a compound of Formula (I) or a saltthereof.

In some embodiments, step (b) is carried out in the presence of a base.

In some embodiments, step (b) is carried out in the presence of atertiary amine.

In some embodiments, step (b) is carried out in the presence oftriethylamine.

In some embodiments, step (b) is carried out in the presence of acatalyst.

In some embodiments, step (b) is carried out in the presence of2-hydroxypyridine.

In some embodiments, step (b) is carried out in the presence ofN,N-dimethylaminopyridine.

In some embodiments, step (b) is carried out at a temperature of about20° C. to about reflux temperature.

In some embodiments, step (b) is carried out at a temperature of about40° C. to about reflux temperature.

In some embodiments, step (b) is carried out at a temperature of about60° C. to about 80° C.

In some embodiments, step (b) is carried out in an amide-formingsolvent.

In some embodiments, step (b) is carried out in an aprotic solvent.

In some embodiments, (b) is carried out in acetonitrile.

In some embodiments, the molar ratio of the compound of Formula (II) tothe compound of Formula (III) is about 2:1 to about 0.5:1.

In some embodiments, the molar ratio of said compound of Formula (II) tosaid compound of Formula (III) is about 1:1.

Salt Formation

One aspect of the present invention pertains to processes for preparingsalts of compounds of Formula (I):

comprising reacting a compound of Formula (I) with a salt-forming acidto form a salt of a compound of Formula (I) provided that thesalt-forming acid is not trifluoroacetic acid.

In some embodiments, the compound of Formula (I) is the R enantiomer.

In some embodiments, the compound of Formula (I) is the S enantiomer.

In some embodiments, the compound of Formula (I) is selected from: the Renantiomer, the S enantiomer or a mixture thereof.

In some embodiments, the salt of a compound of Formula (I) is thehydrochloride salt.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out in a salt-forming solvent.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out in a salt-forming alcohol.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out in isopropanol.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out in ethanol.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out at a temperature of about −10° C. toabout reflux temperature.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out at a temperature of about 10° C. toabout 70° C.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out at a temperature of about 20° C. toabout 60° C.

In some embodiments, the reacting a compound of Formula (I) with asalt-forming acid is carried out at a temperature of about 30° C. toabout 50° C.

In some embodiments, the salt-forming acid is hydrochloric acid.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1, l-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, formamide,N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide,propionitrile, ethyl formate, methyl acetate, hexachloroacetone,acetone, ethyl methyl ketone, ethyl acetate, sulfolane,N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene,or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,o, m-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by one skilledin the art. Reaction temperatures will depend on, for example, themelting and boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures).

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto one skilled in the art.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, propiolic acid, butyric acid, 2-butynoic acid,vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Salts of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization (for example, diastereomeric salt resolution) using a“chiral resolving acid” which is an optically active, salt-formingorganic acid. Suitable resolving agents for fractional recrystallizationmethods are, for example, optically active acids, such as the D and Lforms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid or the various optically activecamphorsulfonic acids such as β-camphorsulfonic acid. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of β-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention and salts thereof can also include allisotopes of atoms occurring in the intermediates or final salts.Isotopes include those atoms having the same atomic number but differentmass numbers. For example, isotopes of hydrogen include tritium anddeuterium.

Compounds of the invention and salts thereof can also include tautomericforms, such as keto-enol tautomers. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

Pharmaceutically Acceptable Salts

One aspect of the present invention pertains to pharmaceuticallyacceptable salts of compounds of Formula (I):

provided that the pharmaceutically acceptable salt is not atrifluoroacetate salt.

One aspect of the present invention pertains to hydrochloride salts ofcompounds of Formula (I).

In some embodiments, the compound of Formula (I) is the R enantiomer.

In some embodiments, the compound of Formula (I) is the S enantiomer.

In some embodiments, the compound of Formula (I) is selected from: the Renantiomer, the S enantiomer or a mixture thereof.

In some embodiments, R¹ is bromo.

In some embodiments, R¹ is chloro.

In some embodiments, the hydrochloride salt has a purity of 80% orgreater.

In some embodiments, the hydrochloride salt has a purity of 90% orgreater.

In some embodiments, the hydrochloride salt has a purity of 95% orgreater.

In some embodiments, the hydrochloride salt has a purity of 99% orgreater.

In some embodiments, the hydrochloride salt has a purity of 99.5% orgreater.

In some embodiments, the hydrochloride salt comprises a hydrochloridesalt of a compound of Formula (I) and the compound of Formula (I) in aratio of about 4:1 or greater.

In some embodiments, the hydrochloride salt comprises a hydrochloridesalt of a compound of Formula (I) and the compound of Formula (I) in aratio of about 9:1 or greater.

In some embodiments, the hydrochloride salt comprises a hydrochloridesalt of a compound of Formula (I) and the compound of Formula (I) in aratio of about 19:1 or greater.

In some embodiments, the hydrochloride salt comprises a hydrochloridesalt of a compound of Formula (I) and the compound of Formula (I) in aratio of about 99:1 or greater.

Intermediates

One aspect of the present invention pertains to intermediates that areuseful in the preparation of compounds of Formula (I) and salts thereof.

Some embodiments pertain to hydrobromide salts of a compound of Formula(II):

In some embodiments, the compound of Formula (II) is the R enantiomer.

In some embodiments, the compound of Formula (II) is the S enantiomer.

In some embodiments, the compound of Formula (II) is selected from: theR enantiomer, the S enantiomer or a mixture thereof.

In some embodiments, the hydrobromide salt has a purity of 80% orgreater.

In some embodiments, the hydrobromide salt has a purity of 90% orgreater.

In some embodiments, the hydrobromide salt has a purity of 95% orgreater.

In some embodiments, the hydrobromide salt has a purity of 99% orgreater.

In some embodiments, the hydrobromide salt has a purity of 99.5% orgreater.

Some aspects of the present invention pertain to compositions comprisinga hydrobromide salt of a compound of Formula (II).

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 10% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 25% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 50% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 75% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 90% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 95% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 99% or greater.

In some embodiments, the composition comprising a hydrobromide salt of acompound of Formula (II) has a purity of 99.5% or greater.

Some embodiments pertain to compounds of Formula (III):

-   -   or a salt thereof, wherein:        -   R¹ is halogen; and        -   R² is 1H-imidazol-1-yl.

In some embodiments, R¹ is chloro.

In some embodiments, R¹ is bromo.

In some embodiments, the compound of Formula (III) has a purity of 80%or greater.

In some embodiments, the compound of Formula (III) has a purity of 90%or greater.

In some embodiments, the compound of Formula (III) has a purity of 95%or greater.

In some embodiments, the compound of Formula (III) has a purity of 99%or greater.

In some embodiments, the compound of Formula (III) has a purity of 99.5%or greater.

Some aspects of the present invention pertain to compositions comprisinga compound of Formula (III).

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 1% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 10% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 25% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 50% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 75% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 90% or greater.

In some embodiments, the composition comprising a compound of Formula(II) has a purity of 95% or greater.

In some embodiments, the composition comprising a compound of Formula(III) has a purity of 99% or greater.

In some embodiments, the composition comprising a compound of Formula(II) has a purity of 99.5% or greater.

Indications and Methods of Treatment

In addition to the foregoing beneficial uses for the modulators of5-HT_(2A) serotonin receptor activity disclosed herein, the saltsdisclosed herein are believed to be useful in the treatment of severaladditional diseases and disorders, and in the amelioration of symptomsthereof. Without limitation, these include the following:

1. Sleep Disorders

It is reported in the National Sleep Foundation's 2002 Sleep In AmericaPoll, more than one-half of the adults surveyed (58%) report havingexperienced one or more symptoms of insomnia at least a few nights aweek in the past year. Additionally, about three in ten (35%) say theyhave experienced insomnia-like symptoms every night or almost everynight.

The normal sleep cycle and sleep architecture can be disrupted by avariety of organic causes as well as environmental influences. Accordingto the International Classification of Sleep Disorders, there are over80 recognized sleep disorders. Of these, salts of the present inventionare effective, for example, in any one or more of the following sleepdisorders (ICSD—International Classification of Sleep Disorders:Diagnostic and Coding Manual. Diagnostic Classification SteeringCommittee; American Sleep Disorders Association, 1990):

A. Dyssomnias

a. Intrinsic Sleep Disorders:

Psychophysiological insomnia, sleep state misperception, idiopathicinsomnia, obstructive sleep apnea syndrome, central sleep apneasyndrome, central alveolar hypoventilation syndrome, periodic limbmovement disorder, restless leg syndrome and intrinsic sleep disorderNOS (not otherwise specified).

b. Extrinsic Sleep Disorders:

Inadequate sleep hygiene, environmental sleep disorder, altitudeinsomnia, adjustment sleep disorder, insufficient sleep syndrome,limit-setting sleep disorder, sleep onset association disorder,nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder,stimulant-dependent sleep disorder, alcohol-dependent sleep disorder,toxin-induced sleep disorder and extrinsic sleep disorder NOS.

c. Circadian Rhythm Sleep Disorders:

Time zone change (jet lag) syndrome, shift work sleep disorder,irregular sleep-wake pattern, delayed sleep phase syndrome, advancedsleep phase syndrome, non-24-hour sleep-wake disorder and circadianrhythm sleep disorder NOS.

B. Parasomnias

a. Arousal Disorders:

Confusional arousals, sleepwalking and sleep terrors.

b. Sleep-Wake Transition Disorders:

Rhythmic movement disorder, sleep starts, sleep talking and nocturnalleg cramps.

C. Sleep Disorders Associated with Medical/Psychiatric Disorders

a. Associated with Mental Disorders:

Psychoses, mood disorders, anxiety disorders, panic disorders andalcoholism.

b. Associated with Neurological Disorders:

Cerebral degenerative disorders, dementia, Parkinsonism, fatal familialinsomnia, sleep-related epilepsy, electrical status epilepticus of sleepand sleep-related headaches.

c. Associated with Other Medical Disorders:

Sleeping sickness, nocturnal cardiac ischemia, chronic obstructivepulmonary disease, sleep-related asthma, sleep-related gastroesophagealreflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis,rheumatoid arthritis, fibromyalgia and post-surgical.

The effects of sleep deprivation are more than excessive daytimesleepiness. Chronic insomniacs report elevated levels of stress,anxiety, depression and medical illnesses (National Institutes ofHealth, National Heart, Lung, and Blood Institute, Insomnia Facts Sheet,October 1995). Preliminary evidence suggests that having a sleepdisorder that causes significant loss of sleep may contribute toincreased susceptibility to infections due to immunosuppression,cardiovascular complications such as hypertension, cardiac arrhythmias,stroke, and myocardial infarction, compromised glucose tolerance,increased obesity and metabolic syndrome. Salts of the present inventionare useful to prevent or alleviate these complications by improvingsleep quality.

The most common class of medications for the majority of sleep disordersare the benzodiazepines, but the adverse effect profile ofbenzodiazepines include daytime sedation, diminished motor coordination,and cognitive impairments. Furthermore, the National Institutes ofHealth Consensus conference on Sleeping Pills and Insomnia in 1984 havedeveloped guidelines discouraging the use of such sedative-hypnoticsbeyond 4-6 weeks because of concerns raised over drug misuse,dependency, withdrawal and rebound insomnia. Therefore, it is desirableto have a pharmacological agent for the treatment of insomnia, which ismore effective and/or has fewer side effects than those currently used.In addition, benzodiazepines are used to induce sleep, but have littleto no effect on the maintenance of sleep, sleep consolidation or slowwave sleep. Therefore, sleep maintenance disorders are not currentlywell treated.

Clinical studies with agents of a similar mechanism of action as aresalts of the present invention have demonstrated significantimprovements on objective and subjective sleep parameters in normal,healthy volunteers as well as patients with sleep disorders and mooddisorders [Sharpley A. L., et al. Slow Wave Sleep in Humans: Role of5-HT_(2A) and 5HT_(2C) Receptors. Neuropharmacology, 1994, Vol.33(3/4):467-71; Winokur A., et al. Acute Effects of Mirtazapine on SleepContinuity and Sleep Architecture in Depressed Patients: A Pilot Study.Soc. of Biol. Psych., 2000, Vol. 48:75-78; and Landolt H. P., et al.Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist onEEG Power Spectra. Neuropsychopharmacology, 1999, Vol. 21(3):455-66].

Some sleep disorders are sometimes found in conjunction with otherconditions and accordingly those conditions are treatable by salts ofcompounds of Formula (I). For example, but not limited to, patientssuffering from mood disorders typically suffer from a sleep disorderthat can be treatable by salts of compounds of Formula (I). Having onepharmacological agent which treats two or more existing or potentialconditions, as does the present invention, is more cost effective, leadsto better compliance and has fewer side effects than taking two or moreagents.

It is an object of the present invention to provide a therapeutic agentfor the use in treating sleep disorders. It is another object of thepresent invention to provide one pharmaceutical agent, which may beuseful in treating two or more conditions wherein one of the conditionsis a sleep disorder. Salts of the present invention described herein maybe used alone or in combination with a mild sleep inducer (i.e.antihistamine).

Sleep Architecture

Sleep comprises two physiological states: Non rapid eye movement (NREM)and rapid eye movement (REM) sleep. NREM sleep consists of four stages,each of which is characterized by progressively slower brain wavepatterns, with the slower patterns indicating deeper sleep. So calleddelta sleep, stages 3 and 4 of NREM sleep, is the deepest and mostrefreshing type of sleep. Many patients with sleep disorders are unableto adequately achieve the restorative sleep of stages 3 and 4. Inclinical terms, patients' sleep patterns are described as fragmented,meaning the patient spends a lot of time alternating between stages 1and 2 (semi-wakefulness) and being awake and very little time in deepsleep. As used herein, the term “fragmented sleep architecture” means anindividual, such as a sleep disorder patient, spends the majority oftheir sleep time in NREM sleep stages 1 and 2, lighter periods of sleepfrom which the individual can be easily aroused to a waking state bylimited external stimuli. As a result, the individual cycles throughfrequent bouts of light sleep interrupted by frequent awakeningsthroughout the sleep period. Many sleep disorders are characterized by afragmented sleep architecture. For example, many elderly patients withsleep complaints have difficulty achieving long bouts of deep,refreshing sleep (NREM stages 3 and 4) and instead spend the majority oftheir sleep time in NREM sleep stages 1 and 2.

In contrast to fragmented sleep architecture, as used herein the term“sleep consolidation” means a state in which the number of NREM sleepbouts, particularly Stages 3 and 4, and the length of those sleep boutsare increased, while the number and length of waking bouts aredecreased. In essence, the architecture of the sleep disorder patient isconsolidated to a sleeping state with increased periods of sleep andfewer awakenings during the night and more time is spent in slow wavesleep (stages 3 and 4) with fewer oscillation stage 1 and 2 sleep. Saltsof the present invention can be effective in consolidating sleeppatterns so that the patient with previously fragmented sleep can nowachieve restorative, delta-wave sleep for longer, more consistentperiods of time.

As sleep moves from stage 1 into later stages, heart rate and bloodpressure drop, metabolic rate and glucose consumption fall, and musclesrelax. In normal sleep architecture, NREM sleep makes up about 75% oftotal sleep time; stage 1 accounting for 5-10% of total sleep time,stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%.About 90 minutes after sleep onset, NREM sleep gives way to the firstREM sleep episode of the night. REM makes up approximately 25% of totalsleep time. In contrast to NREM sleep, REM sleep is characterized byhigh pulse, respiration, and blood pressure, as well as otherphysiological patterns similar to those seen in the active waking stage.Hence, REM sleep is also known as “paradoxical sleep.” Sleep onsetoccurs during NREM sleep and takes 10-20 minutes in healthy youngadults. The four stages of NREM sleep together with a REM phase form onecomplete sleep cycle that is repeated throughout the duration of sleep,usually four or five times. The cyclical nature of sleep is regular andreliable: a REM period occurs about every 90 minutes during the night.However, the first REM period tends to be the shortest, often lastingless than 10 minutes, whereas the later REM periods may last up to 40minutes. With aging, the time between retiring and sleep onset increasesand the total amount of night-time sleep decreases because of changes insleep architecture that impair sleep maintenance as well as sleepquality. Both NREM (particularly stages 3 and 4) and REM sleep arereduced. However, stage 1 NREM sleep, which is the lightest sleep,increases with age.

As used herein, the term “delta power” means a measure of the durationof EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and isthought to be a measure of deeper, more refreshing sleep. Delta power ishypothesized to be a measure of a theoretical process called Process Sand is thought to be inversely related to the amount of sleep anindividual experiences during a given sleep period. Sleep is controlledby homeostatic mechanisms; therefore, the less one sleeps the greaterthe drive to sleep. It is believed that Process S builds throughout thewake period and is discharged most efficiently during delta power sleep.Delta power is a measure of the magnitude of Process S prior to thesleep period. The longer one stays awake, the greater Process S or driveto sleep and thus the greater the delta power during NREM sleep.However, individuals with sleep disorders have difficulty achieving andmaintaining delta wave sleep, and thus have a large build-up of ProcessS with limited ability to discharge this buildup during sleep. 5-HT_(2A)agonists tested preclinically and clinically mimic the effect of sleepdeprivation on delta power, suggesting that subjects with sleepdisorders treated with a 5-HT_(2A) inverse agonist or antagonist will beable to achieve deeper sleep that is more refreshing. These same effectshave not been observed with currently marketed pharmacotherapies. Inaddition, currently marketed pharmacotherapies for sleep have sideeffects such as hangover effects or addiction that are associated withthe GABA receptor. 5-HT_(2A) inverse agonists do not target the GABAreceptor and so these side effects are not a concern.

Subjective and Objective Determinations of Sleep Disorders:

There are a number of ways to determine whether the onset, duration orquality of sleep (e.g. non-restorative or restorative sleep) is impairedor improved. One method is a subjective determination of the patient,e.g., do they feel drowsy or rested upon waking. Other methods involvethe observation of the patient by another during sleep, e.g., how longit takes the patient to fall asleep, how many times the patient wakes upduring the night, how restless is the patient during sleep, etc. Anothermethod is to measure the stages of sleep objectively usingpolysomnography.

Polysomnography is the monitoring of multiple electrophysiologicalparameters during sleep and generally includes measurement of EEGactivity, electroculographic activity and electromyographic activity, aswell as other measurements. These results, along with observations, canmeasure not only sleep latency (the amount of time required to fallasleep), but also sleep continuity (overall balance of sleep andwakefulness) and sleep consolidation (percent of sleeping time spent indelta-wave or restorative sleep) which may be an indication of thequality of sleep.

There are five distinct sleep stages, which can be measured bypolysomnography: rapid eye movement (REM) sleep and four stages ofnon-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4). Stage 1 NREMsleep is a transition from wakefulness to sleep and occupies about 5% oftime spent asleep in healthy adults. Stage 2 NREM sleep, which ischaracterized by specific EEG waveforms (sleep spindles and Kcomplexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREMsleep (also known collectively as slow-wave sleep and delta-wave sleep)are the deepest levels of sleep and occupy about 10-20% of sleep time.REM sleep, during which the majority of vivid dreams occur, occupiesabout 20-25% of total sleep.

These sleep stages have a characteristic temporal organization acrossthe night. NREM stages 3 and 4 tend to occur in the first one-third toone-half of the night and increase in duration in response to sleepdeprivation. REM sleep occurs cyclically through the night. Alternatingwith NREM sleep about every 80-100 minutes. REM sleep periods increasein duration toward the morning. Human sleep also variescharacteristically across the life span. After relative stability withlarge amounts of slow-wave sleep in childhood and early adolescence,sleep continuity and depth deteriorate across the adult age range. Thisdeterioration is reflected by increased wakefulness and stage 1 sleepand decreased stages 3 and 4 sleep.

In addition, the salts of the invention can be useful for the treatmentof the sleep disorders characterized by excessive daytime sleepinesssuch as narcolepsy. Inverse agonists at the serotonin 5-HT_(2A) receptorimprove the quality of sleep at nighttime which can decrease excessivedaytime sleepiness.

Accordingly, another aspect of the present invention relates to thetherapeutic use of salts of the present invention for the treatment ofsleep disorders. Salts of the present invention are potent inverseagonists at the serotonin 5-HT_(2A) receptor and can be effective in thetreatment of sleep disorders by promoting one or more of the following:reducing the sleep onset latency period (measure of sleep induction),reducing the number of nighttime awakenings, and prolonging the amountof time in delta-wave sleep (measure of sleep quality enhancement andsleep consolidation) without effecting REM sleep. In addition, salts ofthe present invention can be effective either as a monotherapy or incombination with sleep inducing agents, for example but not limited to,antihistamines.

Pharmacodynamic Effects of the Selective 5-HT_(2A) Inverse AgonistAPD125 in Healthy Adults

APD125, a potent and selective 5-HT_(2A) serotonin receptor inverseagonist is a member of the genus disclosed in the European PatentEP1558582. In Phase 1 trials, APD125 showed vigilance-lowering effectson waking EEG, with maximal effects at 40-80 mg; peak effects wereobserved at 2-4 h after dosing. In the afternoon nap model of insomniain normal volunteers, APD125 increased slow wave sleep and associatedparameters in a dose-dependent manner, primarily during the early partof sleep. These effects occurred at the expense of REM sleep. Sleeponset latency was not decreased by APD125. In the afternoon nap model,APD125 decreased microarousals, the number of sleep stage shifts, andnumber of awakenings after sleep onset.

In a Phase 2 trial, when compared to placebo, patients treated withAPD125 experienced statistically significant improvements inmeasurements of sleep maintenance, or the ability to maintain sleepduring the night after falling asleep. The improvements in measurementsof sleep maintenance were achieved without any limiting next daycognitive effects. The data from the APD125 Phase 2 study are consistentwith Phase 1 data and support further development of APD125 for thetreatment of insomnia patients who have difficulty maintaining sleep.

In conclusion, APD125, a 5-HT_(2A) serotonin receptor inverse agonist,improved parameters of sleep consolidation and maintenance in humans.Thus, salts of the present invention, also highly selective 5-HT_(2A)serotonin receptor inverse agonists, will offer similar improvements insleep parameters.

2. Antiplatelet Therapies (Conditions Related to Platelet Aggregation)

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does notreceive enough oxygen-rich blood because of a blockage in the coronaryblood vessels. If taken while an attack is in progress or immediatelyafterward (preferably within 30 minutes), antiplatelets can reduce thedamage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter-based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrhythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

5-HT_(2A) serotonin receptors are expressed on smooth muscle of bloodvessels and 5-HT secreted by activated platelets causes vasoconstrictionas well as activation of additional platelets during clotting. There isevidence that a 5-HT_(2A) inverse agonist will inhibit plateletaggregation and thus be a potential treatment as an antiplatelet therapy(see Satimura, K., et al., Clin. Cardiol. 2002 Jan. 25 (1):28-32; andWilson, H. C. et al., Thromb. Haemost. 1991 Sep. 2; 66(3):355-60).

5-HT_(2A) inverse agonists can be used to treat, for example,claudication or peripheral artery disease as well as cardiovascularcomplications (see Br. Med. J. 298: 424-430, 1989), arterial thrombosis(see, Pawlak, D. et al. Thrombosis Research 90: 259-270, 1998),atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23-31,2003), vasoconstriction caused by serotonin (see, Fujiwara, T. andChiba, S. Journal of Cardiovascular Pharmacology 26: 503-510, 1995),restenosis of arteries following angioplasty or stent placement (see,Fujita, M. et al. Am. Heart J. 145:e16, 2003). It can also be used aloneor in combination with thrombolytic therapy, for example, tissueplasminogen activator (tPA) (see, Yamashita, T. et al. Haemostasis30:321-332, 2000), to provide cardioprotection following MI orpostischemic myocardial dysfunction (see, Muto, T. et al. Mol. Cell.Biochem. 272: 119-132, 2005) or protection from ischemic injury duringpercutaneous coronary intervention (see, Horibe, E. Circulation Research68: 68-72, 2004), and the like, including complications resultingtherefrom.

5-HT_(2A) inverse antagonists can increase circulating adiponectin inpatients, suggesting that they would also be useful in protectingpatients against indications that are linked to adiponectin, forexample, myocardial ischemia reperfusion injury and atherosclerosis (seeNomura et al. Blood Coagulation and Fibrinolysis 2005, 16, 423-428).

The 5-HT_(2A) inverse agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereofcomprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein. In further embodiments, thepresent invention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein at a time where such riskexists.

3. Asthma

5-HT (5-hydroxytryptamine) has been linked to the pathophysiology ofacute asthma (see Cazzola, M. and Matera, M. G., Trends Pharmacol. Sci.21: 201-202, 2000; and De Bie, J. J. et al., British J. Pharm., 1998,124, 857-864). The salts of the present invention disclosed herein areuseful in the treatment of asthma, and the treatment of the symptomsthereof. Accordingly, in some embodiments, the present inventionprovides methods for treating asthma in a patient in need of thetreatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In furtherembodiments, methods are provided for treating a symptom of asthma in apatient in need of the treatment, comprising administering to thepatient a composition comprising a 5-HT_(2A) inverse agonist disclosedherein.

4. Agitation

Agitation is a well-recognized behavioral syndrome with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and uncooperativeness (See Cohen-Mansfield J., and Billig, N.,(1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J.Am. Geriatr. Soc. 34(10): 711-721).

Agitation is a common occurrence in the elderly and is often associatedwith dementia such as those caused by Alzheimer's disease, Lewy Body,Parkinson's, and Huntington's, which are degenerative diseases of thenervous system. Diseases that affect blood vessels, such as stroke, ormulti-infarct dementia, which is caused by multiple strokes in the braincan also induce agitation. Alzheimer's disease accounts forapproximately 50 to 70% of all dementias (See Koss E., et al., (1997),Assessing patterns of agitation in Alzheimer's disease patients with theCohen-Mansfield Agitation Inventory. The Alzheimer's Disease CooperativeStudy. Alzheimer Dis. Assoc. Disord. 11(suppl 2): S45-S50).

An estimated 5% of people aged 65 and older and up to 20% of those aged80 and older are affected by dementia; of these sufferers, nearly halfexhibit behavioral disturbances, such as agitation, wandering andviolent outbursts.

Agitated behaviors can also be manifested in cognitively intact elderlypeople and by those with psychiatric disorders other than dementia.

Agitation is often treated with antipsychotic medications such ashaloperidol in nursing home and other assisted care settings. There isemerging evidence that agents acting at the 5-HT_(2A) serotoninreceptors in the brain have the effects of reducing agitation inpatients, including Alzheimer's dementia (See Katz, I. R., et al., J.Clin. Psychiatry 1999 February, 60(2):107-115; and Street, J. S., etal., Arch. Gen. Psychiatry 2000 October, 57(10):968-976).

The salts of the invention disclosed herein are useful for treatingagitation and symptoms thereof. Thus, in some embodiments, the presentinvention provides methods for treating agitation in a patient in needof such treatment comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments, the agitation is due to a psychiatric disorder other thandementia. In some embodiments, the present invention provides methodsfor treatment of agitation or a symptom thereof in a patient sufferingfrom dementia comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments of such methods, the dementia is due to a degenerativedisease of the nervous system, for example and without limitation,Alzheimer's disease, Lewy Body, Parkinson's disease, and Huntington'sdisease, or dementia due to diseases that affect blood vessels,including, without limitation, stroke and multi-infarct dementia. Insome embodiments, methods are provided for treating agitation or asymptom thereof in a patient in need of such treatment, where thepatient is a cognitively intact elderly patient, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein.

5. Add-on Therapy to Haloperidol in the Treatment of Schizophrenia andother Disorders

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked by anumber of characteristics, psychotic symptoms, progression, phasicdevelopment and deterioration in social behavior and professionalcapability in the region below the highest level ever attained.Characteristic psychotic symptoms are disorders of thought content(multiple, fragmentary, incoherent, implausible or simply delusionalcontents or ideas of persecution) and of mentality (loss of association,flight of imagination, incoherence up to incomprehensibility), as wellas disorders of perceptibility (hallucinations), of emotions(superficial or inadequate emotions), of self-perception, of intentionsand impulses, of interhuman relationships, and finally psychomotoricdisorders (such as catatonia). Other symptoms are also associated withthis disorder: see, American Statistical and Diagnostic Handbook.

Haloperidol (Haldol) is a potent dopamine D₂ receptor antagonist. It iswidely prescribed for acute schizophrenic symptoms, and is veryeffective for the positive symptoms of schizophrenia. However, Haldol isnot effective for the negative symptoms of schizophrenia and mayactually induce negative symptoms as well as cognitive dysfunction. Inaccordance with some methods of the invention, adding a 5-HT_(2A)inverse agonist concomitantly with Haldol will provide benefitsincluding the ability to use a lower dose of Haldol without losing itseffects on positive symptoms, while reducing or eliminating itsinductive effects on negative symptoms, and prolonging relapse to thepatient's next schizophrenic event.

Haloperidol is used for treatment of a variety of behavioral disorders,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorders, psychosis (organic and NOS), psychoticdisorder, psychosis, schizophrenia (acute, chronic and NOS). Furtheruses include in the treatment of infantile autism, Huntington's chorea,and nausea and vomiting from chemotherapy and chemotherapeuticantibodies. Administration of 5-HT_(2A) inverse agonists disclosedherein with haloperidol also will provide benefits in these indications.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient a dopamine D₂ receptorantagonist and a 5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient haloperidol and a5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, Huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient a dopamine D₂ receptor antagonist and a 5-HT_(2A) inverseagonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, Huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient haloperidol and a 5-HT_(2A) inverse agonist disclosedherein.

In further embodiments, the present invention provides methods fortreating schizophrenia in a patient in need of the treatment comprisingadministering to the patient a dopamine D₂ receptor antagonist and a5-HT_(2A) inverse agonist disclosed herein. Preferably, the dopamine D₂receptor antagonist is haloperidol.

The administration of the dopamine D₂ receptor antagonist can beconcomitant with administration of the 5-HT_(2A) inverse agonist, orthey can be administered at different times. Those of skill in the artwill easily be able to determine appropriate dosing regimes for the mostefficacious reduction or elimination of deleterious haloperidol effects.In some embodiments, haloperidol and the 5-HT_(2A) inverse agonist areadministered in a single dosage form, and in other embodiments, they areadministered in separate dosage forms.

The present invention further provides methods of alleviating negativesymptoms of schizophrenia induced by the administration of haloperidolto a patient suffering from schizophrenia, comprising administering tothe patient a 5-HT_(2A) inverse agonist as disclosed herein.

6. Diabetic-Related Pathologies

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), increasedplasma serotonin concentration in diabetic patients has also beenimplicated to play a role in disease progression (Pietraszek, M. H., etal. Thrombosis Res. 1992, 66(6), 765-74; and Andrzejewska-Buczko J., etal., Klin. Oczna. 1996; 98(2), 101-4). Serotonin is believed to play arole in vasospasm and increased platelet aggregability. Improvingmicrovascular blood flow is beneficial to diabetic complications.

A recent study by Cameron and Cotter in Naunyn Schmiedebergs Arch.Pharmacol. 2003 June; 367(6):607-14, used a 5-HT_(2A) antagonistexperimental drug AT-1015, and other non-specific 5-HT_(2A) antagonistsincluding ritanserin and sarpogrelate. These studies found that allthree drugs were able to produce a marked correction (82.6-99.7%) of a19.8% sciatic motor conduction deficit in diabetic rats. Similarly,44.7% and 14.9% reductions in sciatic endoneurial blood flow andsaphenous sensory conduction velocity were completely reversed.

In a separate patient study, sarpogrelate was evaluated for theprevention of the development or progression of diabetic nephropathy(Takahashi, T., et al., Diabetes. Res. Clin. Pract. 2002 November;58(2):123-9). In the trial of 24 months of treatment, sarpogrelatesignificantly reduced urinary albumin excretion level.

7. Glaucoma

Topical ocular administration of 5-HT₂ receptor antagonists result in adecrease in intra ocular pressure (IOP) in monkeys (Chang et al., J.Ocul. Pharmacol. 1:137-147 (1985)) and humans (Mastropasqua et al.,Acta. Ophthalmol. Scand. Suppl. 224:24-25 (1997)) indicating utility forsimilar compounds such as 5-HT_(2A) inverse agonists in the treatment ofocular hypertension associated with glaucoma. The 5-HT₂ receptorantagonist ketanserin (Mastropasqua supra) and sarpogrelate (Takenaka etal., Investig. Ophthalmol. Vis. Sci. 36:S734 (1995)) have been shown tosignificantly lower IOP in glaucoma patients.

8. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a lethaldemyelinating disease caused by an opportunistic viral infection ofoligodendrocytes in immunocompromised patients. The causative agent isJC virus, a ubiquitous papovavirus that infects the majority of thepopulation before adulthood and establishes a latent infection in thekidney. In immunocompromised hosts, the virus can reactivate andproductively infect oligodendrocytes. This previously rare condition,until 1984 reported primarily in persons with underlyinglymphoproliferative disorders, is now more common because it occurs in4% of patients with AIDS. Patients usually present with relentlesslyprogressive focal neurologic defects, such as hemiparesis or visualfield deficits, or with alterations in mental status. On brain MRI, oneor more white matter lesions are present; they are hyperintense onT2-weighted images and hypointense on T1-weighted images. There is nomass effect, and contrast enhancement is rare. Diagnosis can beconfirmed by brain biopsy, with demonstration of virus by in situhybridization or immunocytochemistry. Polymerase chain reactionamplification of JC virus sequences from the CSF can confirm diagnosiswithout the need for biopsy [Antinori et al., Neurology (1997)48:687-694; Berger and Major, Seminars in Neurology (1999) 19:193-200;and Portegies, et al., Eur. J. Neurol. (2004) 11:297-304]. Currently,there is no effective therapy. Survival after diagnosis is about 3 to 5months in AIDS patients.

JC virus enters cells by receptor-mediated clathrin-dependentendocytosis. Binding of JC virus to human glial cells (e.g.,oligodendrocytes) induces an intracellular signal that is critical forentry and infection by a ligand-inducible clathrin-dependent mechanism[Querbes et al., J. Virology (2004) 78:250-256]. Recently, 5-HT_(2A) wasshown to be the receptor on human glial cells mediating infectious entryof JC virus by clathrin-dependent endocytosis [Elphick et al., Science(2004) 306:1380-1383]. 5-HT_(2A) antagonists, including ketanserin andritanserin, inhibited JC virus infection of human glial cells.Ketanserin and ritanserin have inverse agonist activity at 5-HT_(2A).

5-HT_(2A) antagonists including inverse agonists have been contemplatedto be useful in the treatment of PML [Elphick et al., Science (2004)306:1380-1383]. Prophylactic treatment of HIV-infected patients with5-HT_(2A) antagonists is envisioned to prevent the spread of JC virus tothe central nervous system and the development of PML. Aggressivetherapeutic treatment of patients with PML is envisioned to reduce viralspread within the central nervous system and prevent additional episodesof demyelination.

One aspect of the present invention encompasses methods for thetreatment of progressive multifocal leukoencephalopathy in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a salt according to any of theembodiments described herein or a pharmaceutical composition.

In some embodiments, the individual in need thereof has alymphoproliferative disorder.

In some embodiments, the lymphoproliferative disorder is leukemia orlymphoma. In some embodiments, the leukemia or lymphoma is chroniclymphocytic leukemia, Hodgkin's disease, or the like.

In some embodiments, the individual in need thereof has amyeloproliferative disorder.

In some embodiments, the individual in need thereof has carcinomatosis.

In some embodiments, the individual in need thereof has a granulomatousor inflammatory disease. In some embodiments, the granulomatous orinflammatory disease is tuberculosis or sarcoidosis.

In some embodiments, the individual in need thereof isimmunocompromised. In some embodiments, the immunocompromised individualhas impaired cellular immunity. In some embodiments, the impairedcellular immunity comprises impaired T-cell immunity.

In some embodiments, the individual in need thereof is infected withHIV. In some embodiments, the HIV-infected individual has a CD4+ cellcount of ≤200/mm³. In some embodiments, the HIV-infected individual hasAIDS. In some embodiments, the HIV-infected individual has AIDS-relatedcomplex (ARC). In certain embodiments, ARC is defined as the presence oftwo successive CD4+ cell counts below 200/mm³ and at least two of thefollowing signs or symptoms: oral hairy leukoplakia, recurrent oralcandidiasis, weight loss of at least 15 lb or 10% of body weight withinlast six months, multidermatomal herpes zoster, temperature above 38.5°C. for more than 14 consecutive days or more than 15 days in a 30-dayperiod, or diarrhea with more than three liquid stools per day for atleast 30 days [see, e.g., Yamada et al., Clin. Diagn. Virol. (1993)1:245-256].

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy. In some embodiments, the immunosuppressivetherapy comprises administering an immunosuppressive agent [see, e.g.,Mueller, Ann. Thorac. Surg. (2004) 77:354-362; and Krieger and Emre,Pediatr. Transplantation (2004) 8:594-599]. In some embodiments, theimmunosuppressive therapy comprises administering an immunosuppressiveagent selected from the group consisting of: corticosteroids (forexample, prednisone and the like), calcineurin inhibitors (for example,cyclosporine, tacrolimus, and the like), antiproliferative agents (forexample, azathioprine, mycophenolate mofetil, sirolimus, everolimus, andthe like), T-cell depleting agents (for example, OKT®3 monoclonalantibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-1H (anti-CD52)mAb, anti-CD4 mAb, anti-T cell receptor mAb, and the like), anti-IL-2receptor (CD25) mAb (for example, basiliximab, daclizumab, and thelike), inhibitors of co-stimulation (for example, CTLA4-Ig, anti-CD154(CD40 ligand) mAb, and the like), deoxyspergualin and analogs thereof(for example, 15-DSG, LF-08-0299, LF14-0195, and the like), leflunomideand analogs thereof (for example, leflunomide, FK778, FK779, and thelike), FTY720, anti-alpha-4-integrin monoclonal antibody, and anti-CD45RB monoclonal antibody. In some embodiments, the immunosuppressive agentand said salt or pharmaceutical composition are administered in separatedosage forms. In some embodiments, the immunosuppressive agent and saidsalt or pharmaceutical composition are administered in a single dosageform.

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy after organ transplantation. In someembodiments, the organ is liver, kidney, lung, heart, or the like [see,e.g., Singh et al., Transplantation (2000) 69:467-472].

In some embodiments, the individual in need thereof is undergoingtreatment for a rheumatic disease. In some embodiments, the rheumaticdisease is systemic lupus erythematosus or the like.

In some embodiments, the salt or the pharmaceutical composition inhibitsJC virus infection of human glial cells

9. Hypertension

Serotonin has been observed to play an important role in the regulationof vascular tone, vasoconstriction, and pulmonary hypertension (Deuchar,G. et al. Pulm. Pharmacol. Ther. 18(1):23-31. 2005; and Marcos, E. etal. Circ. Res. 94(9):1263-70 2004). Ketanserin, a 5-HT_(2A) inverseagonist, have been demonstrated to protect against circulatory shocks,intracranial hypertension, and cerebral ischemia during heatstroke(Chang, C. et al. Shock 24(4): 336-340 2005); and to stabilize bloodpressure in spontaneously hypertensive rats (Miao, C. Clin. Exp.Pharmacol. Physiol. 30(3): 189-193). Mainserin, a 5-HT_(2A) inverseagonist, has been shown to prevent DOCA-salt induced hypertension inrats (Silva, A. Eur, J. Pharmacol. 518(2-3): 152-7 2005).

10. Pain

5-HT_(2A) inverse agonists are also effective for the treatment of pain.Sarpogrelate has been observed to provide a significant analgesic effectboth on thermal induced pain in rats after intraperitonealadministration and on inflammatory pain in rats after either intrathecalor intraperitoneal administration (Nishiyama, T. Eur. J. Pharmacol.516:18-22 2005). This same 5-HT_(2A) inverse agonist in humans has beenshown to be an effective treatment for lower back pain, leg pain andnumbness associated with sciatica brought on by lumbar disc herniation(Kanayama, M. et al. J. Neurosurg.: Spine 2:441-446 2005).

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more salts as described herein and one ormore pharmaceutically acceptable carriers. Some embodiments pertain topharmaceutical compositions comprising a salt of the present inventionand a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one saltaccording to any of the salt embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active salt(s) with liquids or finely divided solidcarriers, or both, in the required proportions and then, if necessary,forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the salt of the invention in a suitable liquid vehicle andfilter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A salt of the present invention can be formulated into pharmaceuticalcompositions using techniques well known to those in the art. Suitablepharmaceutically-acceptable carriers, outside those mentioned herein,are known in the art; for example, see Remington, The Science andPractice of Pharmacy, 20^(th) Edition, 2000, Lippincott Williams &Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, asalt of the invention may, in an alternative use, be administered as araw or pure chemical, it is preferable however to present the salt oractive ingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a salt of the invention or a solvate, hydrate or derivativethereof together with one or more pharmaceutically acceptable carriersthereof and/or prophylactic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not overly deleterious to the recipient thereof.Typical procedures for making and identifying suitable hydrates andsolvates, outside those mentioned herein, are well known to those in theart; see for example, pages 202-209 of K. J. Guillory, “Generation ofPolymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphismin Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker,Inc., New York, 1999, incorporated herein by reference in its entirety.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The salts of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive salts or principles and such unit dosage forms may contain anysuitable effective amount of the active ingredient commensurate with theintended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Salts of the present invention or a solvate, hydrate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2A) receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and is intended to mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the salts of the present invention can varywithin-wide limits and as is customary and is known to the physician, itis to be tailored to the individual conditions in each individual case.It depends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the salt employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active salts are administered inaddition to the salts of the present invention. Representative doses ofthe present invention include, but not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular salt employed,whether a drug delivery system is utilized, on whether an acute orchronic disease state is being treated or prophylaxis is conducted or onwhether further active salts are administered in addition to the saltsof the present invention and as part of a drug combination. The dosageregimen for treating a disease condition with the salts and/orcompositions of this invention is selected in accordance with a varietyfactors as cited above. Thus, the actual dosage regimen employed mayvary widely and therefore may deviate from a preferred dosage regimenand one skilled in the art will recognize that dosage and dosage regimenoutside these typical ranges can be tested and, where appropriate, maybe used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The salts of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a salt of the invention or a solvate or hydratethereof.

For preparing pharmaceutical compositions from the salts of the presentinvention, the selection of a suitable pharmaceutically acceptablecarrier can be either solid, liquid or a mixture of both. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size. The powders and tablets may contain varyingpercentage amounts of the active salt. A representative amount in apowder or tablet may contain from 0.5 to about 90 percent of the activesalt; however, an artisan would know when amounts outside of this rangeare necessary. Suitable carriers for powders and tablets are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter and the like.The term “preparation” is intended to include the formulation of theactive salt with encapsulating material as carrier providing a capsulein which the active component, with or without carriers, is surroundedby a carrier, which is thus in association with it. Similarly, cachetsand lozenges are included. Tablets, powders, capsules, pills, cachetsand lozenges can be used as solid forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The salts according to the present invention may thus be formulated forparenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the salts according to theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the salts of the presentinvention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thesalts of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the salts of thepresent invention in water, water/alcohol mixtures or suitable salinesolutions can be employed using customary additives, for example benzylalcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the salt will generally have a smallparticle size for example of the order of 10 microns or less. Such aparticle size may be obtained by means known in the art, for example bymicronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the salt in a suitable powderbase such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Pharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts may be prepared from pharmaceutically acceptablenon-toxic acids including inorganic and organic acids. Representativeacids include, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalSciences, 66:1-19 (1977), incorporated herein by reference in itsentirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The salts of this invention may form solvates with standard lowmolecular weight solvents using methods known to the skilled artisan.

Salts of the present invention can be converted to “pro-drugs.” The term“pro-drugs” refers to salts that have been modified with specificchemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as salts of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the salt. In onegeneral aspect, the “pro-drug” approach is utilized to facilitate oralabsorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one salt according to any of the salt embodimentsdisclosed herein, together with at least one known pharmaceutical agentas described herein and a pharmaceutically acceptable carrier.

It is noted that when the 5-HT_(2A) receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as 5-HT_(2A)receptor modulators, for the treatment of an 5-HT_(2A)-associateddisease or disorder in companionship animals (e.g., cats, dogs, etc.)and in livestock animals (e.g., cows, chickens, fish, etc.) Those ofordinary skill in the art are readily credited with understanding theutility of such salts in such settings.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Illustrated syntheses of the present invention are shown Scheme 1 wherethe symbols have the same definitions as used throughout thisdisclosure.

The syntheses are further illustrated by the following examples. Thefollowing examples are provided to further define the invention without,however, limiting the invention to the particulars of these examples.The compounds and salts thereof described herein, supra and infra, arenamed according to the CS ChemDraw Ultra Version 7.0.1, AutoNom version2.2, or CS ChemDraw Ultra Version 9.0.7. In certain instances commonnames are used and it is understood that these common names would berecognized by those skilled in the art.

Chemical shifts of proton nuclear magnetic resonance (¹H NMR) spectraare given in parts per million (ppm) with the residual solvent signalused as reference. NMR abbreviations are used as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, bs=broad singlet.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1 Preparation of 4-Chloro-1-methyl-1H-pyrazole-3-carboxylic AcidStep A: Preparation of Ethyl 4-Ethoxy-2-oxo-3-butenoate

To a solution of triethylamine (444 mL, 4.39 mol) in ethyl vinyl ether(1.7 L) under a nitrogen atmosphere was added ethyl oxalyl chloride (500g, 3.66 mol) dropwise over 1 h. After complete addition, the reactionbecame exothermic and started to reflux. Once the exotherm had subsidedthe reaction mixture was allowed to stir at room temperature for anadditional 2 h. After complete reaction, the mixture was diluted withMTBE (1.2 L) and the resultant triethylammonium chloride precipitate wasfiltered and washed twice with MTBE (2×500 mL). The combined filtrateswere concentrated under reduced pressure to give crudeethyl-4-ethoxy-2-oxo-3-butenoate (655 g) as viscous orange oil. This oilwas used crude in the subsequent reaction. ¹H-NMR (400 MHz, DMSO-d₆) δ7.85 (d, J=12.6 Hz, 1H), 5.99 (d, J=12.6 Hz, 1H), 4.24 (q, J=7.0 Hz,2H), 4.11(q, J=7.0 Hz, 2H), 1.30-1.20 (m, 6H).

Step B: Preparation of 1H-Pyrazole-3-carboxylic Acid Ethyl Ester

A suspension of hydrazine hydrochloride (250 g, 3.65 mol) in methanol(1.5 L) was heated to reflux under nitrogen. At reflux, crude ethyl4-ethoxy-2-oxo-3-butenoate (655 g, 3.65 mol) was added dropwise over 2h. After complete addition, the reaction was allowed to cool to roomtemperature with stirring. After 2 h, the reaction was complete and itwas cooled to 5° C. (ice bath) and the resulting precipitate wasfiltered and then washed with methanol (100 mL) to provide the firstcrop of the title compound (containing unreacted hydrazinehydrochloride, which was later removed by washing with water). Thecombined filtrates were concentrated under reduced pressure to give abrown syrupy residue (about 400 mL). Water (1.2 L) was added to thesyrup and the mixture stirred for 30 min. The resulting solid wasfiltered under suction to provide a second crop of the title compound.The two product crops were combined and washed with water (2×100 mL) toafford the title compound as a beige solid (241 g, 47% over two steps)containing up to 15% w/w of 1H-pyrazole-3-carboxylic acid methyl ester.¹H-NMR (400 MHz, DMSO-d₆) δ 13.57 (bs, 1H), 7.82 (m, 1H), 6.76 (m, 1H),4.26 (q, J=7.1 Hz, 2H), 3.80 (s, methyl ester impurity), 1.29 (t, J=7.1Hz, 3H).

Step C: Preparation of 4-Chloro-1H-Pyrazole-3-carboxylic Acid EthylEster

A 5 L flange flask fitted with an overhead stirrer, condenser andtemperature probe was charged with 1H-pyrazole-3-carboxylic acid ethylester (326 g, 2.33 mol) and N,N-dimethylformamide (1.86 L). Thesuspension was stirred and heated to 40° C. internal temperature undernitrogen causing the precipitate to dissolve. Once dissolved, solidN-chlorosuccinimide (NCS) (342 g, 2.56 mol) was added portionwise (10-15g portions) over 2 h, maintaining the reaction temperature <45° C. Whenall the NCS had been added, the reaction was allowed to cool slowly to20° C. over 16 h. Once complete consumption of starting material hadbeen achieved, the reaction mixture was cooled to about 15° C. and thenwith vigorous stirring, water (1.9 L) was added over 10 minutes. Thesuspension was stirred for a further 20 min and then filtered through asinter funnel under suction. The filter cake was carefully washed twicewith water (2×750 mL) and then with heptanes (1×500 mL). The filter cakewas air dried and then transferred to a vacuum oven and dried overnight(60° C., 9 mBar). The title compound was isolated as an off-white solid(330 g, 1.89 mol, 81%) containing an impurity,4-chloro-1H-pyrazole-3-carboxylic acid methyl ester. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.3 (bs, 1H, minor tautomer), 13.8 (bs, 1H, majortautomer), 7.95 (bs, 1H, major tautomer), 7.77 (bs, 1H, minor tautomer),4.40-4.20 (m, 2H, overlapping tautomers), 3.40-3.25 (bs, methyl esterimpurity), 1.40-1.20 (m, 3H, overlapping tautomers).

Step D: Preparation of 4-Chloro-1-methyl-1H-pyrazole-3-carboxylic AcidEthyl Ester

A 5 L flange flask fitted with an overhead stirrer, pressure equalizingdropping funnel, condenser and temperature probe was charged with4-chloro-1H-pyrazole-3-carboxylic acid ethyl ester (330 g, 1.89 mol),anhydrous potassium carbonate (784 g, 5.67 mol) and 2-methyltetrahydrofuran (2 L). The dropping funnel was charged with iodomethane(537 g, 3.78 mol), as a thin stream to the reaction mixture over 1 h.Following complete addition, the reaction was stirred at 20° C. for 16h. Once the reaction was complete, the suspension was filtered through asinter funnel and the cake washed twice with tetrahydrofuran (2×660 mL).The combined filtrates were concentrated to about 10% of the originalvolume under reduced pressure then heptane (660 mL) was added withmixing. After aging for 10 minutes, the light brown precipitate wasfiltered under suction, and the cake was washed with further heptanes(660 mL) and air-dried. The cake was further dried under reducedpressure (60° C., 9 mBar) to afford the title compound as a light-browncrystalline solid (331 g, 1.696 mol, 93%) containing an impurity,4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester. ¹H-NMR(400 MHz, DMSO-d₆): δ 8.12 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.89 (s,3H), 3.34 (s, methyl ester impurity), 1.28 (t, J=7.1 Hz, 3H).

Step E: Preparation of 4-Chloro-1-methyl-1H-pyrazole-3-carboxylic Acid

Method 1: A 5 L flange flask fitted with an overhead stirrer, pressureequalizing dropping funnel and a temperature probe was charged with4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (309 g,1.640 mol) and propan-2-ol (1.55 L). The mixture was gently warmed to aninternal temperature of 45° C. and then a solution of NaOH (131 g, 3.28mol) in deionized water (930 mL) was added over 30 min. The mixture wasstirred and heated at 45° C. for an additional 2.5 h until all thestarting material had been consumed. The reaction mixture was partiallyconcentrated under reduced pressure, and the propan-2-ol removed. Theremaining solution was added with stirring to a solution of concentratedHCl (520 mL) in deionized water (1.5 L). The resulting white precipitatewas stirred at room temperature for 48 h. The precipitate was thenfiltered under suction and the crude product combined with two otherbatches prepared as above. The wet, crude product (800 g) wasrecrystallized by dissolving in glacial acetic acid (2.8 L) with heatingto 80° C. Once dissolved, deionized water (1 L) was added and then thehot solution was poured, with vigorous stirring into water (3 L). Oncecooled-to-room temperature, the grey precipitate was filtered undersuction, washed with additional water (2×1 L) and heptanes (1×500 mL)and then transferred to a vacuum oven for further drying (24-36 h, 70°C., 9 mBar) to give the title compound (363 g, 54%). The filtratesolution (AcOH/H₂O) was concentrated under reduced pressure, until moreprecipitate appeared which was filtered under suction on a sinterfunnel. The filter cake was washed with water (1 L) and the off-whitesolid dried in a vacuum oven (24 h, 70° C., 9 mBar) to leave a secondcrop of the title compound (103 g, 15%). The combined filtrates wereevaporated to dryness and the residue recrystallized from hot deionizedwater (2.5 L, 85° C.). Upon cooling to 10° C., the white precipitate wasfiltered under suction and then dried in a vacuum oven (24 h, 70° C., 9mBar) to leave a third crop of the title compound (39 g, 6%). A finalevaporation of aq. HCl solution and any other remaining filtratesprovided additional product (13%). Therefore a total of 592 g of thetitle compound (88%) was isolated. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.95(s, 1H), 8.08 (s, 1H), 3.90 (s, 3H).

Method 2: A 10 L flange flask fitted with an overhead stirrer, pressureequalizing dropping funnel and a temperature probe was charged with4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (489 g,2.593 mol) and 2-methyltetahydrofuran (3 L). The mixture was warmed to40° C., stirred until dissolved and then an aqueous solution of KOH (291g, 5.185 mol) in deionized water (1.5 L) was added over 15 minutes. Atthis point, to assist stirring, additional water (1 L) was added andstirring was continued for 16 h. Once complete, the organic phase wasseparated and discarded. The basic aqueous phase was acidified byaddition to cooled, vigorously stirred 4 M HCl (1.4 L). After completeaddition, the precipitate was stirred for an additional 1 h at roomtemperature, filtered, washed with water (3×1 L), heptane (1 L) and thenair-dried (2 h). The cake was further dried under reduced pressure (48h, 80° C., 9 mBar) to afford the title compound as a white crystallinesolid (384 g, 93%). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.95 (s, 1H), 8.08 (s,1H), 3.90 (s, 3H).

Example 2 Preparation of(S)-1-(4-Fluorophenyl)-2-(3-methylpiperazin-1-yl) ethanone hydrobromide

In a 5 L three-neck reactor equipped with a stirrer, a thermocouple, acooling bath, an addition funnel and a nitrogen inlet was placed(S)-2-methylpiperazine (175 g, 1.753 mol) and isopropanol (3.2 L). Themixture was cooled and stirred well at 4° C. in an isopropanol/ice bath.4′-Fluoro-2-bromoacetophenone (350 g, 1.613 mol) was added portion-wise(25 g each) at such a rate that the reaction temperature was kept atbelow 10° C. After the addition was completed, the reaction was allowedto warm to room temperature and stirred overnight. Isopropanol (500 mL)was then added over a period of 25 to 30 min. 1 h after the addition wascompleted, the reaction was warmed slowly to 45° C. The slurry wasfiltered. The solid was washed with isopropanol and dried in a vacuumoven at 40° C. to provide the title compound (417 g). LCMS m/z=373.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (bs, 2H), 8.06-8.14 (m, 2H),7.34-7.42 (m, 2H), 4.08 (s, 2H), 3.25-3.40 (m, 2H), 2.97-3.05 (m, 3H),2.62-2.68 (m, 1H), 2.41-2.46 (m, 1H), 1.28 (d, J=9, 3H).

Example 3 Preparation of(4-Chloro-1-methyl-1H-pyrazol-3-yl)(1H-imidazol-1-yl)methanone

In a 5 L three-neck reactor equipped with a mechanical stirrer, athermocouple, a heating mantle, a condenser, an addition funnel and anitrogen inlet was placed 4-chloro-1-methyl-1H-pyrazole-3-carboxylicacid (201 g, 1.252 mol) and acetonitrile (2.0 L). Carbonyldiimidazole(198 g, 1.221 mol) was added slowly. After completion of the addition,acetonitrile (100 mL) was added to wash down the residual solids. Thereaction mixture was heated to 55-57° C. for 1 h and cooled to 30-35° C.The product was used in Example 4 infra without further purification.

Example 4 Preparation of(S)-2-(4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanone

(S)-1-(4-Fluorophenyl)-2-(3-methylpiperazin-1-yl) ethanone hydrobromide(397 g, 1.252 mol) and 2-hydroxy pyridine (4.0 g) were added slowly tothe reaction mixture described in Example 3, followed by triethylamine(190 g 1.878 mol). The solution became homogenous. After completion ofaddition, the reaction mixture was heated under nitrogen atmosphere at65° C. overnight. The mixture was concentrated. The residue was dilutedwith water (1 L). The thick slurry was extracted with isopropyl acetate(2×500 mL). The isopropyl acetate layer was washed with NaOH solution(10%, 300 mL), water (250 mL), dried over magnesium sulfate (85 g), andconcentrated under reduced pressure to provide the title compound (456g, 96%). LCMS m/z=379.4 [M+H]⁺.

Example 5 Preparation of(S)-2-(4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanonehydrochloride

(S)-2-(4-(4-Chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanone as crude freebase (456 g) was dissolved in ethanol (1.1 L) withgentle warming. Hydrochloric acid (1.25 M in EtOH, 1170 mL) was added.The reaction mixture was stirred at room temperature overnight. A thickprecipitate of the hydrochloride salt separated out. The thick slurrywas allowed to stand at room temperature overnight and heated slowly to45° C. until the slurry became loose and easy to stir. The slurry wasfiltered warm (40° C.), washed with isopropanol (500 mL), and dried togive the title compound (201 g). A portion of the solvent (about 1100mL) was removed from the mother liquors when more of the hydrochloridesalt precipitated out. The slurry was cooled to room temperature andfiltered. The solid was washed with isopropanol (2×300 mL) and dried togive an additional amount of the title compound (151 g), a total of 352g (70%) combined. The enantiomeric excess as determined by chiral HPLCwas ≥98%. LCMS m/z=379.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.93-10.97(bs, 1H), 8.08-8.12 (m, 2H), 7.47-7.51 (m, 2H), 4.87-5.21 (m, 3H), 4.58(bs, 1.2H), 4.15(bs, 0.8), 3.90 (s, 3H), 3.41-3.80 (m, 3H), 3.05-3.26(bs, 2H), 1.50-1.52 (d, J=6 Hz, 3H).

Chiral HPLC Conditions

-   Column: ChiralPak ADH, 4.6×250 mm, 5 m particle size, with    pre-column filter-   Mobile Phase: 0.05% diethylamine in hexane:methanol:ethanol (90:5:5)-   Flow Rate: 1.0 mL/min-   Sample Concentration: 0.2 mg/mL in mobile phase-   Injection Volume: 20 μl-   Column Temperature: 25° C.-   Detector Wavelength 220 nm-   Retention Times: S-enantiomer=32.6 min.; R-enantiomer=47.0 min.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

What is claimed is:
 1. A process for preparing a compound of Formula(II):

or a salt thereof, comprising reacting a compound of Formula (IV):

wherein: R³ is halogen; with a compound of Formula (V):

or a salt thereof, to form said compound of Formula (II) or a saltthereof.
 2. The process according to claim 1, wherein R³ is bromo. 3.The process according to claim 1, wherein said compound of Formula (V)is the S enantiomer.